Total Synthesis of Cyanthiwigin F

Stoltz

The cyanthiwigins offer a pretty interesting range of biological activities,
including antimicrobial and antineoplastic, along with nerve
growth factor stimulation; Cyanthiwigin F has some moderate cytoxicity
versus human primary tumour cells. Indeed, as Stoltz mentions, it’s surprising that they’ve
only been the product of two syntheses (Andrew
Phillips and
Jagadeeswar Reddy).

Key to Stoltz’s approach is a recognition of an element of centrosymmetry in
the molecule, with the cyclohexanone moiety at its core. Focus on the
quaternary stereocenters, and the position of the double bond, and one can
recognise that there’s something to work with there. Stoltz went one further,
and realised that both stereocenters could be imparted using the same
reagent-controlled asymmetric alkylation. First, they had to make the substrate:

A Dieckmann
condensation dimerised the 1,4-diallyl esters to give the required
1,4-cyclohexanedione functionality very quickly - a nice use of an old school
reaction. This was then bis-methylated in the thermodynamic manner to give the
substrate for Pd catalysis. I must stress
that at this point we have both (R,R), (S,S) and the meso
compound as a statistical mixture.

The first step is
an unselective deallylative decaboxylalion to lose one stereocenter. This gives
an enolate, and a remaining stereocenter, which may be either S or R,
so we’ve got a racemic mixture of enantiomers. Next up, the enolate center is
alkylated using the enantiomerically enriched Pd catalyst to give mostly
the R configuration at the center. So now we’ve got a mixture of
diastereoisomers, R,R and R,S. However, the remaining allyl ester
is then decarboxylated to give the respective enolate - but now we only have one
stereocenter, and it is mostly R. Lastly, the freshly
installed enolate is alkylated, again attaining R configuration to give a
predominance of the desired (R,R) product.

Now, to complete the target. A desymmetrization established a triflate from one
of the carbonyl groups, and allowed a
Negishi coupling with an unsaturated
partner. RCM completed the medium
ring, followed by hydroboration and
oxidation of the remaining terminal olefin to an aldehyde. The aldehyde was then cyclised using a bit of radical chemistry, completing the
final ring.

Lastly, Stoltz did a further triflation and a Pd catalysed coupling reaction
with an i-Pr-organocuprate. This is very similar to Negishi
chemistry, but they describe it as being ‘difficult’, and there’s no reference
cited… An interesting reaction, although details are unknown!

Fantastic total synthesis - and I’ve not even mentioned the lack of protecting groups
until now!